There is currently tremendous enthusiasm for cell-base therapies for heart disease. For example, as of this writing, PubMed cites 6,135 publications under "stem cells &heart", and 434 under "stem cells &heart &clinical trial". Our first application for this grant (7/1/2003) was based on the premise that well designed clinical trials will require additional information about the most effective cells to employ, the optimal route of administration and ---most importantly---the mechanisms whereby the cells repair the heart. Several recent publications have strongly supported our initial premise. As indicated in Progress Report, we have made considerable progress on several of these issues as they relate to cell therapy with the stem/progenitors cells from bone marrow referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). Among our recent discoveries is an explanation for a paradox observed by many investigators: intravenously infused MSCs improve cardiac function in animal models for myocardial infarction (MI) even though most of the cells are trapped in the lung. Our results demonstrate that the MSCs trapped in the lung greatly over-express the multipotent anti-inflammatory gene and protein known as TNF1 stimulated gene 6 (TSG-6) and that the TSG-6 inhibits the proteinase network that is part of the early inflammatory response to MI. Aim 1 will develop further evidence for the role of TSG-6 in the treatment of MI with MSCs. Aim 2 will search for additional cardioprotective factors produced by activated MSCs. Aim 3 will compare intracardiac infusions with intravenous infusion of MSCs and protective factors produced by MSCs. PUBLIC HEALTH RELEVANCE: Myocardial infarction is a leading cause of death and debilitation in the US and worldwide. There is currently tremendous enthusiasm for cell-base therapies for heart disease. However, there is also an urgent need to generate further fundamental information in order to design safe and effective therapies. In the previous funding period of this grant we have generated some of this fundamental information. The present application is to extend this work and to capitalize an unexpected discovery that it may justify infusing therapeutic intravenously, a much more attractive route for therapy than injection into the heart.